1. Field of Invention
This invention is directed to an improved freeze-drying (lyophilization) process. More specifically the instant invention concerns a freeze-drying process wherein cephalothin sodium for parenteral administration is prepared which is essentially crystalline and is rapidly soluble on reconstitution in a conventional acceptable pharmaceutical diluent and has excellent storage stability.
2. Prior Art
Freeze-drying is an old and often used process for removing a solvent from a solute. It provides a method for removing a solvent without damaging heat labile solutes. Antibiotics and other pharmaceuticals have been processed by freeze-drying procedures for three or more decades and foods, particularly instant coffee, have been prepared by this method for many years. Ordinarily, a solution from which it is desired to recover the solute in a relatively solvent-free state is frozen solid and then subjected to an environment of a high vacuum, and the temperature of the environment is raised to provide the units of heat absorbed in the sublimation of the frozen solvent. The temperature of the environment is kept below that which would result in the meltdown of the frozen solution. In practice, the temperature of the environment is coordinated with the vacuum to produce the highest reasonable sublimation rate, avoiding a melting of the frozen mass.
Water is the solvent generally utilized in a freeze-drying process. Other solvents or combinations thereof can be employed but are limited to those which become solid in the range of temperatures which can be employed practically in the process and which will sublime under vacuum.
Although all of the material does not have to be in solution to effectively operate a freeze-drying process, instant coffee being one probable example, this invention is concerned with a process wherein crystalline cephalothin sodium is prepared in a freeze-drying procedure from a true super-saturated solution. In freeze-drying antibiotics and other pharmaceuticals it has been the practice to follow the classic process outlined above; to wit, prepare solution, freeze to solid, subject to high vacuum, add heat, sublime solvent. However, when such a conventional procedure is followed, the process involving cephalothin sodium requires a cycle time of more than 24 hours to achieve a stable crystalline product.
The cephalothin sodium involved in this invention can be recovered from organic solvents, such as those identified above, in an essentially crystalline state. The crystals are equally as stable as the crystals prepared by the freeze-drying process of the instant invention.
However, recovering crystals of cephalothin sodium for use in ampoule preparations for parenteral administration poses other problems and conditions which are both inefficient, difficult and costly. For example, there is no effective way known to sterilize the crystals of cephalothin sodium recovered from organic solvents so the entire crystallization process must be carried out in an aseptic environment. In the large and extensive process required to sterilely crystallize cephalothin sodium there are many opportunities for the admittance of foreign materials into the crystals which later on will show up as particulate matter in a reconstituted ampoule of the antibiotic. No one has yet developed an apparatus for filling dry material into an ampoule which will measure the material going into each ampoule with as good a consistency and precision as can be routinely achieved with liquid filling equipment.
United States Patent Application, Ser. No. 744,552 now abandoned teaches and claims a novel and useful freeze-drying process for preparing crystalline cefazolin sodium for parenteral administration from an ethanol-water solution. Moreover, U.S. Pat. No. 4,029,655 describes a process which embodies a procedure that includes a very rapid cooling of an aqueous solution to nucleate the cephalothin sodium, among other cephalosporins, during the interval that the freezing takes place. Such nucleation crystallizes the bulk of the cephalothin sodium from the solution immediately prior to the solidfication of the water. Consequently, when the sublimation procedure is initiated the cephalothin sodium already exists as crystals and does not depend on the crystallization to take place as the solvent is removed. The solvent is sublimed away and the cephalothin sodium remains behind.
While the process provides a means for obtaining stable sterile crystalline cephalothin sodium for parenteral administration, the process requires more than 24 hours for the completion of one cycle. Consequently, the scheduling of the use of the freeze-drying equipment and the work schedules of the personnel is unsatisfactory because of the irregularity of the operation. Following the teachings of the prior art requires a 28 to 36 hour cycle from the starting of the freeze-drying operation until it is completed. This relatively long time is a source of added cost to the product and annoyance and irritation to the personnel.
Accordingly, it is an object of this invention to provide a process of freeze-drying cephalothin sodium that will result in essentially crystalline powder for reconstitution for parenteral administration and which will permit the turn-around of the freeze-drying equipment every 24 hours or less.
Another object of this invention is to provide a process which will include the liquid filling of a measured volume of a sterile solution of a known concentration of cephalothin sodium into an ampoule wherein such cephalothin sodium is recovered from such solution as an essentially crystalline material for reconstitution for parenteral administration which is storage stable.
Still another object of this invention is to provide an ampoule containing an essentially crystalline cephalothin sodium which is storage stable and which upon reconstitution for parenteral administration is substantially free of foreign particulate matter.